Patent EA-004315-B1 (EA)
Title: Novel sulfonylbenzoic acids and process for preparation of 4-benzamido-pyrazolo-5-carboxamides and use thereof
Inventor: BUNNAGE MARK EDWARD
IPC: C07D231/40
Filed: 1998-04-10
Abstract: 1. A process for the preparation of a compound of formula (IXA) or (IXB): comprising reacting a compound of formula (XA) or (XB) respectively with a compound of formula (XI) wherein R<1> is C1-C3 alkyl substituted with C3-C6 cycloalkyl, CONR<5>R<6> or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrralidinyl, piperidinyl, morpholinyl and 4-R<9>-piperazinyl; (CH2)nHet or (CH2)nAr; R<2> is C1-C6 alkyl; R<3> is C1-C6 alkyl optionally substituted with C1-C4 alkoxy; R<4> is SO2NR<7>R<8>; R<5> and R* are each independently selected from H and C1-C4 alkyl optionally substituted with C1-C4 alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R<9>-piperazinyl group; R<7> and R<8>, together with the nitrogen atom to which they are attached, form a 4-R<10>-piperazinyl group; R<9> is C1-C4 alkyl; R<10> is H or C1-C4 alkyl optionally substituted with OH, C1-C4 alkoxy or CONH2; Het is a C-linked 6-mernbered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C1-C4 alkyl optionally substituted with C1-C4 alkoxy, C1-C4 alkoxy, halo and NH2; Ar is phenyl optionally substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, halo, CN, CONH2, NO2, NH2, NHSO2(C1-C4 alkyl) and SO2NH2: and n is 0 or 1. 2. A process according to claim 1 wherein R<1> is C1-C2 alkyl substituted with C3-C5 cycloalkyl, CONR<5>R<6> or a N-linked heterocyclic group selected from pyrazolyl, triazolyl, morpholinyl and 4-R<9>-piperazinyl; (CH2)nHet or (CH2)nAr; R<5> is H and R<6> is C1-C4 alkyl optionally substituted with C1-C4 alkoxy or R<5> and R<6>, together with the nitrogen atom to which they are attached, form a morpholinyl group; Het is selected from pyridinyl, 1-oxidopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl and oxadiazolyl, any of which is optionally substituted with one or two substituents selected from CH3, CH2CH2OCH3, OCH3 and NH2; and R<2>, R<3>, R<4>, R<9>, Ar and n are as previously defined in claim 1. 3. A process according to claim 2 wherein R<1> is C1-C2 alkyl substituted with cyclobutyl, CONR<5>R<6>, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl; pyrimidin-2-yl; CH2Het or (CH2)NAr: R<2> is C1-C3 alkyl; R<3> is C1-C3 alkyl optionally substituted with C, to C2 alkoxy; R<S> is H and R<6> is C, to C2 alkyl optionally substituted with C1-C2 alkoxy or R<5> and R<6>, together with the nitrogen atom to which they are attached, form a morpholin-4-yl group; R<10> is C1-C2 alkyl optionally monosubstituted with OH, OCH3 or CONH3; Het is selected from pyridin-2-yl, 1-oxidopyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-methylthiazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl, 4-methyl-1,2,4-triazol-3-yl, 3-methyl-1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 4-chorophenyl, 4-bromophenyl, 2-cyanophenyl, 2-carbamoylphenyl, 4-carbamoylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl, 4-(prop-2-ylsulphonamido)phenyl and 4-sulphamoylphenyl; and n is as previously defined in claim 2. 4. A process according to claim 3 wherein R<1> is cyclobutylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl)ethyl, pyrimidin-2-yl, CH2Het or (CH2)nAr; R<2> is CH2CH3 or CH2CH2CH3; R<3> is CH2CH3, CH2CH2CH3 or CH2CH2OCH3; R<10> is CH3, CH2CH3 or CH2CH2OH; Het is selected from pyridin-2-yl, pyridazin-3-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimida2ol-2-y, 3,5-dimethylisoxazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 2-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl and 4-(prop-2-ylsulphonamido)phenyl; and n is as previously defined in claim 3. 5. A compound of formula (XI) wherein R<3> is C1-C6 alkyl optionally substituted with C1-4 alkoxy; R<4> is SO2NR<7>R<8>; R<7> and R<8>, together with the nitrogen atom to which they are attached, form a 4-R<10>-piperazinyl group; R<10> is H or C1-C4 alkyl optionally substituted with OH, C1-C4 alkoxy or CONH2; with the proviso that when R<3>is ethyl, R<4> is not 4-methylpiperizin-1-ylsulfonyl. 6. A compound according to claim 5 wherein R<3> is C1-C3 alkyl optionally substituted with C1-C2 alkoxy; R<10> is C1-C32 alkyl optionally monosubstituted with OH, OCH3 or CONH2. 7. A compound according to claim 6 wherein R<3> is CH2CH3, CH2CH2CH3 or CH2CH2OCH3; R<10> is CH3, CH2CH3 or CH2CH2OH.